Prostanoids generated by COX-2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX-2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX-2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX-2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (ΔU) or ExoU and ExoT (ΔUT). COX-2–/– mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX-2 products such as prostaglandin E2 on the function of phagocytic cells. Our studies indicate that prostaglandin E2 may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E2 suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor–/– mice compared to the wild-type controls. Thus it is possible that inhibition of COX-2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.